Depression is the most prevalent stress-associated mental condition, imposing a serious economic burden on our society. Although there are a number of clinically effective treatments for depression and associated psychiatric conditions, a large segment of patients exhibit treatment-resistance to first-line interventions; limitations in current antidepressants call for novel interventions based on pathological mechanisms of depression. Accumulating evidence suggests that alterations in immune and inflammation processes, including changes in expression of pro- and anti-inflammatory cytokines are observed in patients with depression, whereby high stress environments may exacerbate their perturbed regulation. Consistently, chronic exposure to social defeat stress in rodents induces intracerebral activation of immune and inflammation systems, including elevation of certain cytokines, that are largely regulated by immune cells, including microglia which may underlie depressive animal behaviors. Notably, many natural products used in traditional Eastern medicine, such as Kanpo (adaptation of traditional Chinese medicine, Japan), have been shown to function as anti-inflammatory factors and antidepressants and have been empirically used for treatment and prevention of inflammation-associated human disease, including depression. Nonetheless, there is almost no mechanism-based evidence for the effectiveness of traditional herbal medicines in treatment of depression. Pachyman (1,3-?-Glucans) is a main ingredient of several Eastern medicines, such as Yokukansan. In addition to the evidence of the antidepressant effect of Yokukansan, pachyman is reported to have anti-immune/inflammatory effects. Taken together, understanding the mechanistic link between its antidepressant and anti-inflammatory effects may open a new window for identification of novel preventive and/or treatment targets for depressive symptoms. In this project, we test the hypothesis that pachyman may ameliorate stress-associated immune/inflammation changes, leading to antidepressant effects. We will examine the protective and treatment effect of pachyman on stress-induced microglial immune changes and depressive behaviors using mice subjected to social defeat stress (Aims 1 and 2). Finally, based on our preliminary findings showing the strong suppressive effect of pachyman on stress-induced microglial IL18 expression in the prefrontal cortex, we will investigate whether microglia-specific knockdown of IL18 in the medial prefrontal cortex may ameliorate depressive behaviors induced by chronic social defeat stress. Defining the mechanism of action of pachyman may provide a basis for identifying novel drug targets for the prevention and treatment of depression and related mental conditions.